Project Abstract HAND HIV-associated neurocognitive disorders (HAND) including asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorders (MND) and HIV-associated dementia (HAD) persist despite effective antiretroviral therapy (ART). HAD is markedly decreased but ANI and MND persist and affecting 25-50% of ART-treated individuals. With durable ART, there is emergent evidence of chronic immune system activation that contributes to AIDS-related co-morbidities including HAND and cardiovascular disease (CVD). Chronic immune activation that includes activated monocyte/macrophages and markers on these cells are consistently associated with these comorbidities. While the mechanisms for chronic immune activation with HIV and ART aren?t well understood, microbial translocation, secondary infections and residual viral replication in cell and tissue reservoirs likely play a role. Central to all these mechanisms is activated monocyte/macrophages. In addition to memory CD4+ T cells, macrophages are cellular reservoirs for latent HIV, and the central nervous system (CNS) is a tissue reservoir for HIV- DNA. Thus, there is a great need for adjunctive therapies to be used with cART that target monocyte/macrophage activation, accumulation in parenchymal tissues and latent-replication competent virus. In this proposal we use a rapid AIDS with ART that does not results in encephalitis with 1) methylglyoxal bis(guanylhydrazone) (MGBG) and 2) a rhesus monkey (Rh) anti-?4?1 integrin mAb, as adjunctive therapies targeting activated and infected monocyte/macrophages. Extending findings from our previous funding period, we propose these two approaches; targeting monocyte/macrophage activation and maturation, accumulation in the CNS and blocking SIVE. We propose to define mechanisms by which these adjunctive therapies function. Moreover, we propose to test the ability of MGBG and anti-?4?1 integrin mAb with ART to clear latent, replication competent virus within macrophages within and leaving the CNS, following therapy interruption.